Enamel and dental anomalies in latent-transforming growth factor beta-binding protein 3 mutant mice.

Latent-transforming growth factor beta-binding protein 3 (LTBP-3) is important for craniofacial morphogenesis and hard tissue mineralization, as it is essential for activation of transforming growth factor-β (TGF-β). To investigate the role of LTBP-3 in tooth formation we performed micro-computed tomography (micro-CT), histology, and scanning electron microscopy analyses of adult Ltbp3-/- mice. The Ltbp3-/- mutants presented with unique craniofacial malformations and reductions in enamel formation that began at the matrix formation stage. Organization of maturation-stage ameloblasts was severely disrupted. The lateral side of the incisor was affected most. Reduced enamel mineralization, modification of the enamel prism pattern, and enamel nodules were observed throughout the incisors, as revealed by scanning electron microscopy. Molar roots had internal irregular bulbous-like formations. The cementum thickness was reduced, and microscopic dentinal tubules showed minor nanostructural changes. Thus, LTBP-3 is required for ameloblast differentiation and for the formation of decussating enamel prisms, to prevent enamel nodule formation, and for proper root morphogenesis. Also, and consistent with the role of TGF-β signaling during mineralization, almost all craniofacial bone components were affected in Ltbp3-/- mice, especially those involving the upper jaw and snout. This mouse model demonstrates phenotypic overlap with Verloes Bourguignon syndrome, also caused by mutation of LTBP3, which is hallmarked by craniofacial anomalies and amelogenesis imperfecta phenotypes.journal article2017 Febimporte

Mutations in the latent TGF-beta binding protein 3 (LTBP3) gene cause brachyolmia with amelogenesis imperfecta

Inherited dental malformations constitute a clinically and genetically heterogeneous group of disorders. Here, we report on four families, three of them consanguineous, with an identical phenotype, characterized by significant short stature with brachyolmia and hypoplastic amelogenesis imperfecta (AI) with almost absent enamel. This phenotype was first described in 1996 by Verloes et al. as an autosomal recessive form of brachyolmia associated with AI. Whole-exome sequencing resulted in the identification of recessive hypomorphic mutations including deletion, nonsense and splice mutations, in the LTBP3 gene, which is involved in the TGF-beta signaling pathway. We further investigated gene expression during mouse development and tooth formation. Differentiated ameloblasts synthesizing enamel matrix proteins and odontoblasts expressed the gene. Study of an available knockout mouse model showed that the mutant mice displayed very thin to absent enamel in both incisors and molars, hereby recapitulating the AI phenotype in the human disorder

P2662Factors associated with in-hospital and long-term mortality in STEMI patients: does primary ventricular fibrillation matter?

Abstract Introduction There are still contrary data about causes and long-term prognosis in patients (pts) with primary ventricular fibrillation (PVF) as a complication of ST-elevation myocardial infarction (STEMI). Purpose The aim was to analyze characteristics of STEMI patients associated with PVF occurrence and mortality. Methods Our study included 755 pts hospitalised due to STEMI between January 2016 and December 2016. One year follow up was done. Study compared pts with cardiac arrest due to PVF and those without PVF. Only pts treated with urgent coronarography and primary percutaneous coronary intervention (PPCI) in whom TIMI 3 in infarct-related artery was acheved were included. Pts with Killip class 4 as well as pts with mechanical complications or complications due to procedure were excluded. Results We found 56/755 (7.42%) STEMI pts had PVF. Compared to pts without PVF (n=699), those with PVF (n=56) were younger (57.8±12.9 vs. 61.8±11.9 years, p 0.02) and more frequently had diabetes mellitus (DM) (52.3% vs. 33.4%, p 0.01) alone or DM with abnormal glucoregulation (AGR) (77.3% vs. 58.4%, p 0.01). Pts with STEMI and PVF had more frequently Killip class 2 (32.7% vs. 21.2%, p 0.02) and class 3 (7.3% vs. 3%, p 0.08), most frequently left anterior descending coronary artery affected (51.8% vs. 36.9%, p 0.03) and proximal occlusion of coronary arteries (44.6% vs. 23%, p 0.000), lower left ventricle ejection fraction (LVEF) (45.4±9.8% vs. 48.7±7.5%, p 0.02), longer duration of hospitalisation (7.3±5.7 vs. 5.7±3.2 days, p 0.001) and higher in-hospital mortality (12.5% vs. 4.9%, p 0.02), but with no difference in long-term mortality (14.3% vs. 11.6%, p 0.40). After multivariable logistic regression analysis (MVLR), model with the differences in proximal coronary artery occlusions (OR 2.4 [95% CI: 1.3–4.7], p 0.008) and DM presence (OR 1.9 [95% CI: 1–3.6], p 0.05) persisted. After one year patients who died compared to those still alive were older (70.8±12.8 vs. 61±11.8 years, p 0.000), more frequently male (52% vs. 32.2%, p 0.01), had higher appearance of anterior wall STEMI (46.7% vs. 24.5%, p 0.001), more frequently Killip class 2 and class 3 (50% vs. 20.9% and 23.5 vs. 2.4% respectively, both p 0.000), lower EF (38.6±10.5 vs. 48.8±7.3%) and higher prevalence of DM (75.8% vs. 32.4%) or DM with AGR (87.9% vs. 57.9%) (both p 0.000). After MVLR model with differences in Killip class 3 (OR 4.2 [95% CI: 1.1–84.6], p 0.000), EF (OR 0.93 [95% CI: 0.87–0.99], p 0.04) and DM presence (OR 3.3 [95% CI: 1.1–10.2], p 0.04), all persisted. Conclusions Proximal coronary occlusions and DM presence as indicators of coronary artery disease severity and ischaemic area size are strongly associated with PVF in STEMI patients. Only in-hospital mortality is higher in patients with STEMI and PVF. Long-term mortality in STEMI patients is strongly associated with heart failure (lower EF and higher Killip class) and again DM presence. </jats:sec

Synthesis of 5-azaandrostane-3b,17b-diol protected at the 17b-hydroxyl group

In the present paper, the preparation of 3b-hydroxy-17b-dimethyl-tert-butylsilyloxy-5-azaandrostane (15) in fourteen steps is described. B-nor-17-oxoandrost-5-en-3b-yl acetate (1) was used as the starting material, which was transformed to the key intermediate of the synthesis, B-nor-17b-dimethyl-tert-butylsilyloxyandrost-4-en-3b-yl acetate (7)

5,10:13,14-Disecosteroids: novel modified steroids containing 10- and 9-membered rings

In this paper a synthetic pathway to the modified 5,10 13,14-bisfragmentation cholestane derivatives 8-14 is described. The synthesis involves introduction of the 5 alpha- and 14 alpha-hydroxyl groups in the cholestane molecule and Subsequent cleavage of the C(5)-C(10) bond in 5 alpha,14 alpha-dihydroxycholestan-3 beta-yl acetate (4) with the HgO/I-2 reagent and the C(13)-C( 14) bond in the stereoisomeric 14 alpha-hydroxy-5,10-secosteroids 5 and 6 with the Pb(OAc)(4)/I-2 reagent Complete and Unambiguous H-1 and C-13 NMR resonance assignments of the obtained secosteroids. as well as the Solution conformations of then 10- and 9-membered rings were determined by extensive analysis of 1D and 2D NMR spectral data The structures and the solid-state conformations of 5,10-secosteroids 5-7 were confirmed by X-ray analysis All diseco-compounds have a novel 5.10 13,14-disecocholestane skeleton. (C) 2009 Elsevier Ltd. All rights reserve

Survival and neurological recovery after out-of-hospital cardiac arrest

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Out-of-hospital cardiac arrest (OHCA) is a major public health challenge and although rate of intrahospital survival increased over the last 40 years, it still remains poor (from 8,6% in 1976-1999 to 9,9% in 2000-2019). Different studies report that introduction of mild therapeutic hypothermia (TTM) improves survival and neurological outcome in comatose patients after OHCA.  Purpose The aim of this research was to evaluate influence of pre-hospital predictors related to cardiopulmonary resuscitation (CPR), neurological status and ECG changes at admission and early percutaneous coronary intervention (PCI) performed within 24h of admission on intrahospital survival and neurological outcome of OHCA patients. Methods The research was conducted as a retrospective cohort study of data taken from the hospital registry on OHCA from January 2007 until November 2019. The analyzed factors were: bystander CPR, duration of CPR until return of ROSC, initial rhythm, responsiveness upon admission defined as Glasgow Coma Score (GCS)&amp;gt;8, presence of ST segment elevation (STEMI) on electrocardiography (ECG) and early PCI. The favorable neurological outcome was defined as a cerebral performance category scale (CPC)≤2. Results The research included 506 survivors of OHCA. Cardiac arrest was witnessed in 412 (81.4%), bystander CPR was performed in 197 (38.9%), CPR lasted ≤20min in 291 (57.5%), initial rhythm was shockable in 304 (60.1%) of patients. At admission 387 (76.5%) were comatose (GCS &amp;lt; 8) and TTM was introduced in 177 (45.7%) of patients. ECG upon admission showed STEMI in 176 (34.8%) and early PCI was performed in 145 (28.6%) of patients. In-hospital mortality in our study group was 281 (55.5%) and 185 (36.6%) of patients had favorable neurological outcome. Multivariate regression analysis showed that initial shockable rhythm (OR 3.391 [2.310-4.977], p &amp;lt; 0.0005), early PCI (OR 0.368 [0.226-0.599], p &amp;lt; 0.0005), duration of CPR ≤20min (OR 4.249 [2.688-6.718], p &amp;lt; 0.0005) and GCS &amp;gt; 8 (OR 0.194 [0.110-0.343], p &amp;lt; 0.0005) were independent predictors of in-hospital survival. Independent predictors of favorable neurological outcome were: initial shockable rhythm (OR 3.301 [2.002-5.441], p&amp;lt; 0.0005), STEMI on ECG upon admission (OR 0.528 [0.326-0.853], p = 0.009), duration of CPR ≤20min (OR 5.144 [3.090-8.565], p&amp;lt; 0.0005) and GCS &amp;gt; 8 (OR 0.152 [0.088-0.260], p&amp;lt; 0.0005). Introduction of TTM improved both intrahospital survival (54.1% vs. 24.4%; p &amp;lt; 0.0005) and neurological outcome (33.5% vs. 11.6%; p &amp;lt; 0.0005) in patients with initial shockable rhythm. Conclusion In our study group of OHCA patients of any origin, initial shockable rhythm, duration of CPR ≤20min and GCS &amp;gt; 8 at admission influenced both intrahospital survival and favorable neurological outcome. Introduction of TTM significantly improved both survival and neurological outcome in comatose patients with initial shockable rhythm. </jats:sec

Contemporary review on spontaneous coronary artery dissection: insights into the angiographic finding and differential diagnosis

2023 Kovacevic, Jarakovic, Milovancev, Cankovic, Petrovic, Bjelobrk, Ilic, Srdanovic, Tadic, Dabovic, Crnomarkovic, Komazec, Dracina, Apostolovic, Stanojevic and Kunadian.Spontaneous coronary artery dissection (SCAD), although in the majority of cases presents as an acute coronary syndrome (ACS), has different pathophysiology from atherosclerosis that influences specific angiography findings and enables most patients to be solved by optimal medical therapy rather than percutaneous coronary intervention (PCI). Therefore, accurate diagnosis is essential for adequate treatment of each patient as management of SCAD differs from that of ACS of atherosclerotic aetiology. So far, invasive coronary angiography remains the most important diagnostic tool in suspected SCAD. However, there are ambiguous cases that can mimic SCAD. In this review, the authors summarize current knowledge about the diagnostic algorithms, particularly angiographic features of SCAD, pitfalls of angiography, and the role of intracoronary imaging in the context of SCAD diagnosis. Finally, apart from the pathognomonic angiographic features of SCAD that are thoroughly discussed in this review, the authors focus on obscure angiography findings and findings that can mimic SCAD as well. Differential diagnosis and the timely recognition of SCAD are crucial as there are differences in the acute and long-term management of SCAD and other causes of ACS

P3553Right ventricular echocardiographic composite parameters in predicting major adverse cardiac events in patients with heart failure with reduced ejection fraction

Abstract Background Echocardiography assessment of right ventricle still play an indispensable role in diagnosis, decision-making for further therapy and risk assessment of patients with heart failure with reduced ejection fraction (HFrEF). Aims Our objective was to compare the predictive value of five composite echo parameters of right ventricle (RV) in decompensated patients with HFrEF. Methods and results A total of 191 NYHA III-IV patients admitted for decompensation of advanced HFrEF (EF=25.53±6,87%) were prospectively enrolled. During the follow-up period mean period of 340±84 days, 111 (58.1%) patients met the primary composite endpoint (MACE) of cardiac death, rehospitalization due to repeated decompensation, malignant rhythm disorders, heart attack or stroke. The average time of MACE occurrence was 110.5±98.7 days. Among group of patients with MACE, during the follow-up, there were 34 (30.6%) cardiac related deaths. Re-hospitalization due to cardiovascular causes had 77 patients (69.4%). The study was performed at our hospital between June 2016 and January 2018. Patients were assessed for the following combined echo parameters: (i) relationship of right and left ventricle basal diameter (RVb/LVb x0,1); (ii) relationship of tricuspid annular plane systolic excursion and right ventricle systolic pressure (TAPSE/RVSP mm/mmHg); (iii) relationship of tricuspid annular systolic velocity and right ventricle systolic pressure (TAs'x100/ RVSP cm/s/mmHg); (iv) product of tricuspid annular systolic velocity and pulmonic valve acceleration time (TAs'x PVAcT (cm/s2 x 1000)); (v) product of systolic and diastolic velocity of tricuspid annulus (TAs xTAe). The last three parameters were result of this study and were not mentioned in earlier researches. In this study, univariat analysis of combined RV echo parameters, TAPSE/RVSP, TAs'x100 /RVSP as well as TAs'xPVAcT have been shown to be highly significant predictors of MACE, p=0.001. The TAs'xTAe' product has been also distinguished as a significant predictor of MACE, p=0.04, as well as the ratio RVb/LVb x 0.1, p=0.007. Multivariate analysis of these five combined RV echo parameters shows that significant independent predictor of MACE turned out to be TAs'x100/RVSP (p&lt;0.001, HR = 0.668 (0.531–0.840)). Obtained by reconstruction of the ROC curve (Area = 0.70 (95% CI 0.59–0.75); p&lt;0.001, we have got cut off value of TAs'x100/RVSP = 1.92 (cm/s/mmHg). Kaplan-Meier curves were constructed by comparing the time to the occurrence of MACE. Patients with TAs'x100/RVSP ≤1.92 (cm/s/mmHg) have a significantly worse prognosis (Log Rank p&lt;0.001). Conclusion New variable TAs'x100/RVSP, derived from this research, proved to be the most powerful combined RV echo parameter, independent predictor of one year MACE, with a better predictive value compared to the already described combined parameters in the literature. </jats:sec

Perturbation of transforming growth factor (TGF)-ß1 association with latent TGF-β binding protein yields inflammation and tumors

Transforming growth factor-β (TGF-β) activity is controlled at many levels including the conversion of the latent secreted form to its active state. TGF-β is often released as part of an inactive tripartite complex consisting of TGF-β, the TGF-β propeptide, and a molecule of latent TGF-β binding protein (LTBP). The interaction of TGF-β and its cleaved propeptide renders the growth factor latent, and the liberation of TGF-β from this state is crucial for signaling. To examine the contribution of LTBP to TGF-β function, we generated mice in which the cysteines that link the propeptide to LTBP were mutated to serines, thereby blocking covalent association. Tgfb1C33S/C33S mice had multiorgan inflammation, lack of skin Langerhans cells (LC), and a shortened lifespan, consistent with decreased TGF-β1 levels. However, the inflammatory response and decreased lifespan were not as severe as observed with Tgfb1−/− animals. Tgfb1C33S/C33S mice exhibited decreased levels of active TGF-β1, decreased TGF-β signaling, and tumors of the stomach, rectum, and anus. These data suggest that the association of LTBP with the latent TGF-β complex is important for proper TGF-β1 function and that Tgfb1C33S/C33S mice are hypomorphs for active TGF-β1. Moreover, although mechanisms exist to activate latent TGF-β1 in the absence of LTBP, these mechanisms are not as efficient as those that use the latent complex containing LTBP

Mutations in LTBP4 Cause a Syndrome of Impaired Pulmonary, Gastrointestinal, Genitourinary, Musculoskeletal, and Dermal Development

We report recessive mutations in the gene for the latent transforming growth factor-β binding protein 4 (LTBP4) in four unrelated patients with a human syndrome disrupting pulmonary, gastrointestinal, urinary, musculoskeletal, craniofacial, and dermal development. All patients had severe respiratory distress, with cystic and atelectatic changes in the lungs complicated by tracheomalacia and diaphragmatic hernia. Three of the four patients died of respiratory failure. Cardiovascular lesions were mild, limited to pulmonary artery stenosis and patent foramen ovale. Gastrointestinal malformations included diverticulosis, enlargement, tortuosity, and stenosis at various levels of the intestinal tract. The urinary tract was affected by diverticulosis and hydronephrosis. Joint laxity and low muscle tone contributed to musculoskeletal problems compounded by postnatal growth delay. Craniofacial features included microretrognathia, flat midface, receding forehead, and wide fontanelles. All patients had cutis laxa. Four of the five identified LTBP4 mutations led to premature termination of translation and destabilization of the LTBP4 mRNA. Impaired synthesis and lack of deposition of LTBP4 into the extracellular matrix (ECM) caused increased transforming growth factor-β (TGF-β) activity in cultured fibroblasts and defective elastic fiber assembly in all tissues affected by the disease. These molecular defects were associated with blocked alveolarization and airway collapse in the lung. Our results show that coupling of TGF-β signaling and ECM assembly is essential for proper development and is achieved in multiple human organ systems by multifunctional proteins such as LTBP4